4-hydroxycinnolines are of interest as precursors for the preparation of biologically active materials, such as potential antimalarial drugs and herbicides.
One method for preparing them is that described by W. Borsche and A. Herbert, Annalen der Chemie, volume 546, pages 293-303 (1944): 4-hydroxycinnolines are prepared by diazotizing a 2-aminoacetophenone in an aqueous medium, removing excess nitrous acid, allowing the resulting solution of the diazonium salt to stand overnight, and then heating the solution until the diazonium salt has disappeared. The salt undergoes cyclocondensation, ##STR1## X being the anion of the acid used in the diazotization.
This general method was followed by N. J. Leonard and S. N. Boyd, Jr., in Journal or Organic Chemistry, volume 11, pages 419-428 (1946). They employed either water or aqueous acetic acid as the cyclocondensation medium, and did not heat the solution of the salt. Contemporaneously with their work, K. Schofield and J. C. E. Simpson, Journal of the Chemical Society (London), 1945, pages 512-520, prepared 4-hydroxycinnolines by the Borsche-Herbert method, except that they heated the solution of the diazonium salt, instead of holding it at room temperature. Messrs. Leonard and Boyd point out that while such a procedure accelerates the cyclocondensation, it markedly reduces the yield, while their procedure--holding the solution at room temperature--results in good yields. However, their procedure requires very long reaction times--of the order of 3 to 44 days.
It has now been discovered that good yields are obtained in much shorter times if the pH of the solution of the diazonium salt is maintained within a defined range while the cyclocondensation reaction is proceeding.